Vericiguat reduces electrical and structural remodeling in a rabbit model of atrial fibrillation.

Purpose: The molecular etiology of atrial fibrillation (AF) and its treatment are poorly understood. AF involves both electrical and structural features. Vericiguat can ameliorate cardiac remodeling in heart failure. The effects of vericiguat on AF, however, are unclear. Here, the actions of vericiguat on atrial structural and electrical remodeling in AF and its possible mechanisms were investigated. Methods and Results: Thirty-six rabbits were randomly allocated to four groups, namely, sham, RAP (pacing with 600 beats/min over three weeks), vericiguat-treated (three weeks' pacing plus daily oral dose of 1.5 mg/kg of vericiguat), and vericiguat-treated only. HL-1 cells received rapid pacing with or without vericiguat. Parameters including electrophysiology, echocardiography, histology, Ca2+ levels, and ICaL density, as well as levels of TRPC6, CaN, NFAT4, p-NFAT4, Cav1.2, collagen I, collagen III, and ST2 were measured. Significant changes of above proteins expression level, circulating biochemical indices, Ca2+ concentrations, and ICaL density in both animals and cell models, these effects were significantly restored by vericiguat. Vericiguat also reversed the enlarged atrium and significantly reduced myocardial fibrosis, together with preventing reduced atrial effective refractory periods (AERPs) and AF induction rate. Conclusion: Vericiguat thus ameliorated AF-associated structural and electrical remodeling. These findings suggest the potential of vericiguat for treating AF.

Case report: Persistent ST-segment elevation due to cardiac metastasis from lung cancer.

Patients with secondary cardiac cancer occasionally show ST segment elevation that mimics acute coronary syndrome despite the absence of coronary artery occlusion. We herein describe a rare case of secondary cardiac cancer that presented with ST-segment elevation. An 82-year-old Chinese man was admitted to the hospital with chest discomfort. Electrocardiography (ECG) showed ST segment elevation in the precordial leads and low-voltage QRS complexes in limb leads without the development of Q waves. Unexpectedly, emergency coronary angiography showed no significant stenosis of the coronary arteries. However, fortunately, transthoracic echocardiography (TTE) revealed massive pericardial effusion and a mass at the apex of the ventricular myocardium. Coincidentally, contrast-enhanced chest computed tomography showed primary lung cancer in the left lower lobe, pericardial effusion, and myocardial metastasis at the ventricular apex. The pericardiac fluid contained blood with significantly increased CEA levels and exfoliated tumor cells. The lung histopathological report suggested squamous cell carcinoma. Two months later, the patient died. These findings suggested that the persistent ST-segment without the development of Q waves was associated with ventricular invasion by primary lung cancer and may indicate a poor prognosis. In conclusion, physicians should be aware of persistent ST-segment elevation mimicking myocardial infarction due to cardiac metastasis with a poor prognosis.

Hydrogen Attenuates Thyroid Hormone-Induced Cardiac Hypertrophy in Rats by regulating angiotensin II type 1 receptor and NADPH oxidase 2 mediated oxidative stress.

Cardiac hypertrophy occurs as a result of high levels of thyroid hormone, which may contribute to heart failure and is closely related to oxidative stress. Hydrogen is a good antioxidant. In this study, we found that intragastric levothyroxine administration for two weeks caused obvious cardiac hypertrophy without reduced systolic function. Additionally, hydrogen inhalation ameliorated the levothyroxine-induced metabolic increase and cardiac hypertrophy in rats. Serum brain natriuretic peptide expression was also attenuated by hydrogen treatment. However, hydrogen had no significant effect on levothyroxine -induced serum troponin I and serum thyroid hormone changes. Hydrogen treatment also reduced the levothyroxine-induced increase in cardiac malondialdehyde, 8-hydroxy-2-deoxyguanosine and serum hydrogen peroxide levels and upregulated superoxide dismutase and glutathione peroxidase activity. Additionally, western blotting results showed that hydrogen inhalation inhibited the expression of cardiac nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), angiotensin II type 1 receptor, sarcoplasmic reticulum Ca2+-ATPase (SERCA2), phospho-phospholamban and α-myosin heavy chain proteins. In conclusion, the present study revealed a protective effect of hydrogen on levothyroxine -induced cardiac hypertrophy by regulating angiotensin II type 1 receptors and NOX2-mediated oxidative stress in rats.

Effects of Sacubitril/Valsartan on the Expression of CaMKII/Cav1.2 in Atrial Fibrillation Stimulation Rabbit Model.

Methods: Overall, 18 rabbits were randomly divided into control, pacing (600 beats/min), and pacing+sac/val groups. The rabbits in the pacing+sac/val cohort received oral sac/val (10 mg/kg twice daily) across the 21-day investigation period. After three weeks, the atrial effective refractory period (AERP) and AF induction rate were compared. HL-1 cultures were exposed to fast pacing (24 h) with and without LBQ657 (active sacubitril form)/valsartan. Western blots were used for detecting Cav1.2 and CaMKII expression within atrial muscles of the rabbits and HL-1 cultures of AF model. Results: In comparison to the sham cohort, the AF induction rate was markedly increased together with AERP reduction within pacing cohort. Such changes were markedly rescued through sac/val treatment in pacing+sac/val cohort. The proteomic expression profiles of CaMKII and Cav1.2 showed that the CaMKII expression was markedly upregulated, while Cav1.2 expression was downregulated in the pacing cohort. Importantly, these effects were absent in pacing+sac/val cohort. Conclusion: Results of this study show that sac/val treatment regulates the expression of CaMKII/Cav1.2 and could alter this pathway in atrial rapid electrical stimulation models. Therefore, this investigation could contribute to a novel strategy in AF therapeutics in clinical settings.

Combined Usage of Trimetazidine With 3-Bromopyruvate May Lead to Cardiotoxicity by Activating Oxidative Stress and Apoptosis in Rats.

ABSTRACT: The energy used by the heart is generated mainly by the metabolism of fatty acids and glucose. Trimetazidine (TMZ) inhibits fatty acid metabolism and is used for the treatment of heart diseases such as heart failure. 3-Bromopyruvate (3-BrPA) can suppress glucose metabolism, and it is considered a promising candidate agent for tumor therapy. Because TMZ and 3-BrPA can separately inhibit the 2 main cardiac energy sources, it is necessary to investigate the effects of 3-BrPA combined with TMZ on the heart. Forty male Wistar rats were randomly divided into 4 groups: a control group, a TMZ group, a 3-BrPA group, and a 3-BrPA + TMZ group. Weight was recorded every day, and echocardiography was performed 14 days later. Heart function, the levels of adenosine triphosphate, oxidative stress-related factors (ROS, glutathione, oxidized glutathione, malondialdehyde, superoxide dismutase and total antioxidant capacity), and apoptosis in heart tissues were assessed to evaluate the effects of 3-BrPA and TMZ on the heart. In our study, no obvious changes occurred in the 3-BrPA group or the TMZ group compared with the control group. The combination of 3-BrPA and TMZ worsened heart function, decreased adenosine triphosphate levels, and increased oxidative stress and myocardial apoptosis. In conclusion, 3-BrPA and TMZ are not recommended for concurrent use.

Detection of circRNA Biomarker for Acute Myocardial Infarction Based on System Biological Analysis of RNA Expression.

Acute myocardial infarction (AMI) is myocardial necrosis caused by the persistent interruption of myocardial blood supply, which has high incidence rate and high mortality in middle-aged and elderly people in the worldwide. Biomarkers play an important role in the early diagnosis and treatment of AMI. Recently, more and more researches confirmed that circRNA may be a potential diagnostic biomarker and therapeutic target for cardiovascular diseases. In this paper, a series of biological analyses were performed to find new effective circRNA biomarkers for AMI. Firstly, the expression levels of circRNAs in blood samples of patients with AMI and those with mild coronary stenosis were compared to reveal circRNAs which were involved in AMI. Then, circRNAs which were significant expressed abnormally in the blood samples of patients with AMI were selected from those circRNAs. Next, a ceRNA network was constructed based on interactions of circRNA, miRNA and mRNA through biological analyses to detect crucial circRNA associated with AMI. Finally, one circRNA was selected as candidate biomarker for AMI. To validate effectivity and efficiency of the candidate biomarker, fluorescence in situ hybridization, hypoxia model of human cardiomyocytes, and knockdown and overexpression analyses were performed on candidate circRNA biomarker. In conclusion, experimental results demonstrated that the candidate circRNA was an effective biomarker for diagnosis and therapy of AMI.

Tranilast prevents doxorubicin-induced myocardial hypertrophy and angiotensin II synthesis in rats.

An increase in oxidative stress is an important pathological mechanism of heart injury induced by doxorubicin (DOX). Tranilast is an anti-allergy drug that has been shown to possess good antioxidant activity in previous studies. The overexpression and secretion of chymase by mast cells (MCs) increase the pathological overexpression of angiotensin II (Ang II), which plays a crucial role in myocardial hypertrophy and the deterioration of heart disease. The MC stabilizer tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid; tran) prevents mast cells from degranulating, which may reduce DOX-induced Ang II synthesis. Therefore, in the present study, we hypothesized that tranilast will protect rats from DOX-induced myocardial damage via its antioxidant activity, thereby inhibiting Ang II expression. Thirty male Wistar rats were divided into three groups (n = 10 in each group) that received DOX, a combination of DOX and tranilast or saline (the control group) to test this hypothesis. Tranilast suppressed chymase expression, reduced Ang II levels and prevented the myocardial hypertrophy and the deterioration of heart function induced by DOX. Based on the findings of the present study, the suppression of chymase-dependent Ang-II production and the direct effect of tranilast on the inhibition of apoptosis and fibrosis because of its antioxidant stress capacity may contribute to the protective effect of tranilast against DOX-induced myocardial hypertrophy.

Sacubitril/valsartan attenuates atrial electrical and structural remodelling in a rabbit model of atrial fibrillation.

Atrial structural and electrical remodelling play important roles in atrial fibrillation (AF). Sacubitril/valsartan attenuates cardiac remodelling in heart failure. However, the effect of sacubitril/valsartan on AF is unclear. The aim of this study was to evaluate the effect of sacubitril/valsartan on atrial electrical and structural remodelling in AF and investigate the underlying mechanism of action. Thirty-three rabbits were randomized into sham, RAP, and sac/val groups. HL-1 cells were subjected to control treatment or rapid pacing with or without LBQ657 and valsartan. Echocardiography, atrial electrophysiology, and histological examination were performed. The concentration of Ca2+ and expression levels of calcineurin, NFAT, p-NFAT, Cav1.2, collagen Ⅰ and Ⅲ, ANP, BNP, CNP, NT-proBNP, and ST2 in HL-1 cells, and IcaL in left atrial cells, were determined. We observed that compared to that in the sham group, the atrium and right ventricle were enlarged, myocardial fibrosis was markedly higher, AF inducibility was significantly elevated, and atrial effective refractory periods were shortened in the RAP group. These effects were significantly reversed by sacubitril/valsartan. Compared to that in the sham group, collagen Ⅰ and Ⅲ, NT-proBNP, ST2, calcineurin, and NFAT were significantly up-regulated, while p-NFAT and Cav1.2 were down-regulated in the RAP group, and sacubitril/valsartan inhibited these changes. Ca2+ concentration increased and ICaL density decreased in in vivo and in vitro AF models, reversed by sacubitril/valsartan. Sacubitril/valsartan attenuates atrial electrical remodelling and ameliorates structure remodelling in AF. This study paves the way for the possibility of clinical use of sacubitril/valsartan in AF patients.

Rotenone and 3-bromopyruvate toxicity impacts electrical and structural cardiac remodeling in rats.

3-Bromopyruvate (3-BrPA) is a promising agent that has been widely studied in the treatment of cancer and pulmonary hypertension. Rotenone is a pesticide commonly used on farms and was shown to have anti-cancer activity and delay fibrosis progression in chronic kidney disease in a recent study. However, there are few studies showing the toxicity of rotenone and 3-BrPA in the myocardium. To support further medical exploration, it is necessary to clarify the side effects of these compounds on the heart. This study was designed to examine the cardiotoxicity of 3-BrPA and rotenone by investigating electrical and structural cardiac remodeling in rats. Forty male rats were divided into 4 groups (n = 10 in each group) and injected intraperitoneally with 3-BrPA, rotenone or a combination of 3-BrPA and rotenone. The ventricular effective refractory period (VERP), corrected QT interval (QTc), and ventricular tachycardia/ventricular fibrillation (VT/VF) inducibility were measured. The expression of Cx43, Kir2.1, Kir6.2, DHPRα1, KCNH2, caspase3, caspase9, Bax, Bcl2, and P53 was detected. Masson's trichrome, TUNEL, HE, and PAS staining and transmission electron microscopy were used to detect pathological and ultrastructural changes. Our results showed that rotenone alone and rotenone combined with 3-BrPA significantly increased the risk of ventricular arrhythmias. Rotenone combined with 3-BrPA caused myocardial apoptosis, and rotenone alone and rotenone combined with 3-BrPA caused electrical and structural cardiac remodeling in rats.

Chronic B-Type Natriuretic Peptide Therapy Prevents Atrial Electrical Remodeling in a Rabbit Model of Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is an important and growing clinical problem. Current pharmacological treatments are unsatisfactory. Electrical remodeling has been identified as one of the principal pathophysiological mechanisms that promote AF, but there are no effective therapies to prevent or correct electrical remodeling in patients with AF. In AF, cardiac production and circulating levels of B-type natriuretic peptide (BNP) are increased. However, its functional significance in AF remains to be determined. We assessed the hypotheses that chronic BNP treatment may prevent the altered electrophysiology in AF, and preventing AF-induced activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) may play a role. METHODS AND RESULTS: Forty-four rabbits were randomly divided into sham, rapid atrial pacing (RAP at 600 beats/min for 3 weeks), RAP/BNP, and sham/BNP groups. Rabbits in the RAP/BNP and sham/BNP groups received subcutaneous BNP (20 µg/kg twice daily) during the 3-week study period. HL-1 cells were subjected to rapid field stimulation for 24 hours in the presence or absence of BNP, KN-93 (a CaMKII inhibitor), or KN-92 (a nonactive analog of KN-93). We compared atrial electrical remodeling-related alterations in the ion channel/function/expression of these animals. We found that only in the RAP group, AF inducibility was significantly increased, atrial effective refractory periods and action potential duration were reduced, and the density of ICa, L and Ito decreased, while IK1 increased. The changes in the expressions of Cav1.2, Kv4.3, and Kir2.1 and currents showed a similar trend. In addition, in the RAP group, the activation of CaMKIIδ and phosphorylation of ryanodine receptor 2 and phospholamban significantly increased. Importantly, these changes were prevented in the RAP/BNP group, which were further validated by in vitro studies. CONCLUSIONS: Chronic BNP therapy prevents atrial electrical remodeling in AF. Inhibition of CaMKII activation plays an important role to its anti-AF efficacy in this model.

Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR-α/sirtuin 1/PGC-1α pathway.

BACKGROUND AND PURPOSE: Atrial metabolic remodelling is critical for the process of atrial fibrillation (AF). The PPAR-α/sirtuin 1 /PPAR co-activator α (PGC-1α) pathway plays an important role in maintaining energy metabolism. However, the effect of the PPAR-α agonist fenofibrate on AF is unclear. Therefore, the aim of this study was to determine the effect of fenofibrate on atrial metabolic remodelling in AF and explore its possible mechanisms of action. EXPERIMENTAL APPROACH: The expression of metabolic proteins was examined in the left atria of AF patients. Thirty-two rabbits were divided into sham, AF (pacing with 600 beats·min(-1) for 1 week), fenofibrate treated (pretreated with fenofibrate before pacing) and fenofibrate alone treated (for 2 weeks) groups. HL-1 cells were subjected to rapid pacing in the presence or absence of fenofibrate, the PPAR-α antagonist GW6471 or sirtuin 1-specific inhibitor EX527. Metabolic factors, circulating biochemical metabolites, atrial electrophysiology, adenine nucleotide levels and accumulation of glycogen and lipid droplets were assessed. KEY RESULTS: The PPAR-α/sirtuin 1/PGC-1α pathway was significantly inhibited in AF patients and in the rabbit/HL-1 cell models, resulting in a reduction of key downstream metabolic factors; this effect was significantly restored by fenofibrate. Fenofibrate prevented the alterations in circulating biochemical metabolites, reduced the level of adenine nucleotides and accumulation of glycogen and lipid droplets, reversed the shortened atrial effective refractory period and increased risk of AF. CONCLUSION AND IMPLICATIONS: Fenofibrate inhibited atrial metabolic remodelling in AF by regulating the PPAR-α/sirtuin 1/PGC-1α pathway. The present study may provide a novel therapeutic strategy for AF.